The glycoprotein hormone erythropoietin is of major therapeutic interest, especially for the treatment of anaemia. The protein controls the proliferation and differentiation of erythroid cells through activation of anti apoptotic signals involving JAK/STAT, MAP kinases and PI3 kinases signalling pathways. Since the first usage of rhEPO 20 years ago to treat patients suffering from renal diseases, many investigations have been undertaken to obtain superactive EPO biosimilars that will diminish the administration frequency of the drug.
Hyperglycosylated and pegylated rhEPO have proven very effective in treating anaemia by once- or twice-monthly injections, and the next step in drug research is the development of orally available molecules. Erythropoietin has reduced the need for blood transfusions in cases of anaemia, with dosage of the drug that has proven essential in the treatment of anaemia resulting from cancer chemotherapy. Because of the concomitant findings that tumour cells bear EPOR and that EPO has angiogenic properties additionally to its anti apoptotic effect, fear has arise that EPO could facilitate tumour progression. Such effects have not been demonstrated so far. In the search for orally available drugs, alternative activation of erythropoiesis by acting on EPO transcription elements is a promising strategy, although the control of specificity has proven difficult. Acting on downstream signalling elements of EPOR signalling is another strategy that has only recently been proposed, as well as modifying the trafficking of EPOR after activation by ligand binding. Good perspectives for the treatment of anaemia exists, but the replacement of a very potent molecule (EPO is active at picomolar concentrations) that has already proven very successful during 20 years will not be straitforward.
Erythropoietin has recently shown to induce anti apoptotic signals in non haematopoietic tissues, thus opening new perspectives for the use of EPO or biosimilars in tissue protection.
Effects in neurons, in the kidney and in cardiac cells have been demonstrated and new tissues will certainly be identified as new targets. Use of EPO as tissue protective agent suffers from specificity concerns because of its role in erythropoiesis, but derivatives like carbamoylated EPO that is cardioprotective but lacks erythropoietic activity, are maybe opening a new way in the therapeutic usage of erythropoiesis stimulating agents. Thus, albeit EPO and ESA have been extensively studied and used in the last 20 years to treat anaemia, their therapeutic
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Introduction: Part II: Erythropoietin and erythropoiesis stimulating agentspotential is still expanding and the next challenge is the development of potent EPO derivatives with specific non haematopoietic activities.
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Introduction: Part II: Erythropoietin and erythropoiesis stimulating agentsReferences
1. Carnot, P. and C. De Flandre, Sur l'activité hémopoïetique du sérum au cours de la fégénération du sang. CR Acad Sci Paris, 1906. 143: p. 432-435.
2. Bondsdorff, E. and E. Jalavisto, A humoral mechanism in anoxic erythrocytosis. Physiol Scand, 1948.
5: p. 372-380.
3. Reissmann, K.R., Studies on the mechanism of erythropoietic stimulation in parabiotic rats during hypoxia. Blood, 1950. 5(4): p. 372-80.
4. Jacobson, L.O., et al., Role of the kidney in erythropoiesis. Nature, 1957. 179(4560): p. 633-4.
5. Miyake, T., C.K. Kung, and E. Goldwasser, Purification of human erythropoietin. J Biol Chem, 1977.
252(15): p. 5558-64.
6. Jacobs, K., et al., Isolation and characterization of genomic and cDNA clones of human erythropoietin.
Nature, 1985. 313(6005): p. 806-10.
7. Lin, F.K., et al., Cloning and expression of the human erythropoietin gene. Proc Natl Acad Sci U S A, 1985. 82(22): p. 7580-4.
8. Eschbach, J.W., et al., Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial. N Engl J Med, 1987. 316(2): p. 73-8.
9. Beris, P., EPO: Gene, Molecule and Receptor, in Anaemia in Cancer, C. Bokemeyer and H. Ludwig, Editors. 2005, Elsevier. p. 15-24.
10. Romanowski, R.R. and A.J. Sytkowski, The molecular structure of human erythropoietin. Hematol Oncol Clin North Am, 1994. 8(5): p. 885-94.
11. Dordal, M.S., F.F. Wang, and E. Goldwasser, The role of carbohydrate in erythropoietin action.
Endocrinology, 1985. 116(6): p. 2293-9.
12. Dube, S., J.W. Fisher, and J.S. Powell, Glycosylation at specific sites of erythropoietin is essential for biosynthesis, secretion, and biological function. J. Biol. Chem., 1988. 263(33): p. 17516-17521.
13. Tsuda, E., et al., The role of carbohydrate in recombinant human erythropoietin. Eur J Biochem, 1990.
188(2): p. 405-11.
14. Wasley, L.C., et al., The importance of N- and O-linked oligosaccharides for the biosynthesis and in vitro and in vivo biologic activities of erythropoietin. Blood, 1991. 77(12): p. 2624-2632.
15. Darling, R.J., et al., Glycosylation of erythropoietin affects receptor binding kinetics: role of electrostatic interactions. Biochemistry, 2002. 41(49): p. 14524-31.
16. Lacombe, C., et al., Peritubular cells are the site of erythropoietin synthesis in the murine hypoxic kidney. J Clin Invest, 1988. 81(2): p. 620-3.
17. Maxwell, P.H., et al., Sites of erythropoietin production. Kidney Int, 1997. 51(2): p. 393-401.
18. Tan, C.C., K.U. Eckardt, and P.J. Ratcliffe, Organ distribution of erythropoietin messenger RNA in normal and uremic rats. Kidney Int, 1991. 40(1): p. 69-76.
19. Tan, C.C., et al., Feedback modulation of renal and hepatic erythropoietin mRNA in response to graded anemia and hypoxia. Am J Physiol, 1992. 263(3 Pt 2): p. F474-81.
20. Jelkmann, W. and K. Wagner, Beneficial and ominous aspects of the pleiotropic action of erythropoietin. Ann Hematol, 2004. 83(11): p. 673-86.
21. Zanjani, E.D., et al., Liver as the primary site of erythropoietin formation in the fetus. J Lab Clin Med, 1977. 89(3): p. 640-4.
22. Imagawa, S., et al., Regulatory elements of the erythropoietin gene. Blood, 1991. 77(2): p. 278-85.
23. Wang, G.L. and G.L. Semenza, General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proc Natl Acad Sci U S A, 1993. 90(9): p. 4304-8.
24. Maxwell, P. and P. Ratcliffe, Regulation of expression of the erythropoietin gene. Curr Opin Hematol, 1998. 5(3): p. 166-70.
25. Jelkmann, W., The enigma of the metabolic fate of circulating erythropoietin (Epo) in view of the pharmacokinetics of the recombinant drugs rhEpo and NESP. Eur J Haematol, 2002. 69(5-6): p. 265-74.
26. Gross, A.W. and H.F. Lodish, Cellular trafficking and degradation of erythropoietin and novel erythropoiesis stimulating protein (NESP). J Biol Chem, 2006. 281(4): p. 2024-32.
27. Beris, P., Erythropoiesis and Anaemia, in Anaemia in Cancer, C. Bokemeyer and H. Ludwig, Editors.
2005, Elsevier. p. 3-14.
Oscar Vadas Page 57
Activation of the erythropoietin receptor by multivalent molecules
Introduction: Part II: Erythropoietin and erythropoiesis stimulating agents28. Testa, N.G., Structure and regulation of the erythroid system at the level of progenitor cells. Crit Rev Oncol Hematol, 1989. 9(1): p. 17-35.
29. Cantor, A.B. and S.H. Orkin, Transcriptional regulation of erythropoiesis: an affair involving multiple partners. Oncogene, 2002. 21(21): p. 3368-76.
30. Metcalf, D., Hematopoietic cytokines. Blood, 2008. 111(2): p. 485-491.
31. Adamson, J.W., Erythropoietin: in vitro and in vivo studies of the regulation of erythropoiesis. Soc Gen Physiol Ser, 1988. 43: p. 57-65.
32. Krantz, S.B., Erythropoietin. Blood, 1991. 77(3): p. 419-34.
33. Stopka, T., et al., Human hematopoietic progenitors express erythropoietin. Blood, 1998. 91(10): p.
3766-72.
34. Jelkmann, W., Erythropoietin after a century of research: younger than ever. European Journal of Haematology, 2007. 78(3): p. 183-205.
35. Winearls, C.G., et al., Effect of human erythropoietin derived from recombinant DNA on the anaemia of patients maintained by chronic haemodialysis. Lancet, 1986. 2(8517): p. 1175-8.
36. Markham, A. and H.M. Bryson, Epoetin alfa. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in nonrenal applications. Drugs, 1995. 49(2): p. 232-54.
37. Dunn, C.J. and A. Markham, Epoetin beta. A review of its pharmacological properties and clinical use in the management of anaemia associated with chronic renal failure. Drugs, 1996. 51(2): p. 299-318.
38. Macdougall, I.C., et al., Pharmacokinetics of novel erythropoiesis stimulating protein compared with epoetin alfa in dialysis patients. J Am Soc Nephrol, 1999. 10(11): p. 2392-5.
39. Egrie, J.C. and J.K. Browne, Development and characterization of novel erythropoiesis stimulating protein (NESP). Br J Cancer, 2001. 84 Suppl 1: p. 3-10.
40. Ibbotson, T. and K.L. Goa, Darbepoetin alfa. Drugs, 2001. 61(14): p. 2097-104; discussion 2105-6.
41. Overbay, D.K. and H.J. Manley, Darbepoetin-alpha: a review of the literature. Pharmacotherapy, 2002.
22(7): p. 889-97.
42. Egrie, J.C., et al., Darbepoetin alfa has a longer circulating half-life and greater in vivo potency than recombinant human erythropoietin. Experimental Hematology, 2003. 31(4): p. 290-299.
43. Macdougall, I.C., CERA (Continuous Erythropoietin Receptor Activator): a new erythropoiesis-stimulating agent for the treatment of anemia. Curr Hematol Rep, 2005. 4(6): p. 436-40.
44. Macdougall, I.C., et al., Pharmacokinetics and pharmacodynamics of intravenous and subcutaneous continuous erythropoietin receptor activator (C.E.R.A.) in patients with chronic kidney disease. Clin J Am Soc Nephrol, 2006. 1(6): p. 1211-5.
45. Provenzano, R., et al., The continuous erythropoietin receptor activator (C.E.R.A.) corrects anemia at extended administration intervals in patients with chronic kidney disease not on dialysis: results of a phase II study. Clin Nephrol, 2007. 67(5): p. 306-17.
46. Eschbach, J.W., et al., Treatment of the anemia of progressive renal failure with recombinant human erythropoietin. N Engl J Med, 1989. 321(3): p. 158-63.
47. Macdougall, I.C. and K.-U. Eckardt, Novel strategies for stimulating erythropoiesis and potential new treatments for anaemia. The Lancet, 2006. 368(9539): p. 947-953.
48. Macdougall, I.C., Novel erythropoiesis-stimulating agents: a new era in anemia management. Clin J Am Soc Nephrol, 2008. 3(1): p. 200-7.
49. Smith, R., Applications of darbepoietin-alpha, a novel erythropoiesis-stimulating protein, in oncology.
Curr Opin Hematol, 2002. 9(3): p. 228-33.
50. Taylor, S.K., Is recombinant human erythropoietin (rh-epo) more than just a treatment of anemia in cancer and chemotherapy? Med Hypotheses, 2003. 60(1): p. 89-93.
51. Bohlius, J., et al., Cancer-related anemia and recombinant human erythropoietin--an updated overview.
Nat Clin Pract Oncol, 2006. 3(3): p. 152-64.
52. Adamson, J.W., The anemia of inflammation/malignancy: mechanisms and management. Hematology Am Soc Hematol Educ Program, 2008. 2008: p. 159-65.
53. Mitka, M., FDA sounds alert on anemia drugs. JAMA, 2007. 297(17): p. 1868-9.
54. Spalding, B.J., Changes for ESAs. Nat Biotech, 2008. 26(5): p. 483-483.
55. Melosky, B.L., Erythropoiesis-stimulating agents: benefits and risks in supportive care of cancer. Curr Oncol, 2008. 15(Supplement 1): p. S10-5.
56. Casadevall, N., et al., Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med, 2002. 346(7): p. 469-75.
57. Burton, A., Is it all over for erythropoietin? The Lancet Oncology, 2007. 8(4): p. 285-285.
58. Lenzer, J., Safety of anaemia drug erythropoietin is to be reviewed. BMJ, 2007. 334(7592): p. 495-b-.
Page 58 Oscar Vadas
Activation of the erythropoietin receptor by multivalent molecules
Introduction: Part II: Erythropoietin and erythropoiesis stimulating agents59. Henke, M., et al., Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet, 2003. 362(9392): p. 1255-60.
60. Leyland-Jones, B., et al., Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study. J Clin Oncol, 2005. 23(25): p. 5960-72.
61. Konstantinopoulos, P.A., M.V. Karamouzis, and A.G. Papavassiliou, Selective modulation of the erythropoietic and tissue-protective effects of erythropoietin: time to reach the full therapeutic potential of erythropoietin. Biochim Biophys Acta, 2007. 1776(1): p. 1-9.
62. Anagnostou, A., et al., Erythropoietin has a mitogenic and positive chemotactic effect on endothelial cells. Proc Natl Acad Sci U S A, 1990. 87(15): p. 5978-82.
63. Heeschen, C., et al., Erythropoietin is a potent physiologic stimulus for endothelial progenitor cell mobilization. Blood, 2003. 102(4): p. 1340-6.
64. Bahlmann, F.H., et al., Erythropoietin regulates endothelial progenitor cells. Blood, 2004. 103(3): p.
921-6.
65. Ribatti, D., et al., Human erythropoietin induces a pro-angiogenic phenotype in cultured endothelial cells and stimulates neovascularization in vivo. Blood, 1999. 93(8): p. 2627-36.
66. Watanabe, D., et al., Erythropoietin as a retinal angiogenic factor in proliferative diabetic retinopathy.
N Engl J Med, 2005. 353(8): p. 782-92.
67. Manzoni, P., et al., Erythropoietin as a retinal angiogenic factor. N Engl J Med, 2005. 353(20): p.
2190-1; author reply 2190-1.
68. Grasso, G., et al., Erythropoietin as a tissue-protective cytokine in brain injury: what do we know and where do we go? Neuroscientist, 2004. 10(2): p. 93-8.
69. Maiese, K., F. Li, and Z.Z. Chong, New avenues of exploration for erythropoietin. JAMA, 2005.
293(1): p. 90-5.
70. Masuda, S., et al., Functional erythropoietin receptor of the cells with neural characteristics.
Comparison with receptor properties of erythroid cells. J Biol Chem, 1993. 268(15): p. 11208-16.
71. Leist, M., et al., Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science, 2004. 305(5681): p. 239-42.
72. Genc, S., T.F. Koroglu, and K. Genc, Erythropoietin as a novel neuroprotectant. Restor Neurol Neurosci, 2004. 22(2): p. 105-19.
73. Bartesaghi, S., et al., Erythropoietin: a novel neuroprotective cytokine. Neurotoxicology, 2005. 26(5):
p. 923-8.
74. Brines, M. and A. Cerami, Emerging biological roles for erythropoietin in the nervous system. Nat Rev Neurosci, 2005. 6(6): p. 484-94.
75. Chang, Z.Y., et al., Erythropoiesis-stimulating protein delivery in providing erythropoiesis and neuroprotection. Expert Opin Drug Deliv, 2008. 5(12): p. 1313-1321.
76. Siren, A.L., et al., Therapeutic Potential of Erythropoietin and its Structural or Functional Variants in the Nervous System. Neurotherapeutics, 2009. 6(1): p. 108-127.
77. Ehrenreich, H., et al., Erythropoietin therapy for acute stroke is both safe and beneficial. Mol Med, 2002. 8(8): p. 495-505.
78. Bogoyevitch, M.A., An update on the cardiac effects of erythropoietin cardioprotection by
erythropoietin and the lessons learnt from studies in neuroprotection. Cardiovasc Res, 2004. 63(2): p.
208-16.
79. Hanlon, P.R., et al., Mechanisms of erythropoietin-mediated cardioprotection during ischemia-reperfusion injury: role of protein kinase C and phosphatidylinositol 3-kinase signaling. FASEB J, 2005. 19(10): p. 1323-5.
80. Ratajczak, J., et al., Biological significance of MAPK, AKT and JAK-STAT protein activation by various erythropoietic factors in normal human early erythroid cells. Br J Haematol, 2001. 115(1): p. 195-204.
81. Ammarguellat, F., et al., Low doses of EPO activate MAP kinases but not JAK2-STAT5 in rat vascular smooth muscle cells. Biochem Biophys Res Commun, 2001. 284(4): p. 1031-8.
82. Akimoto, T., et al., Erythropoietin regulates vascular smooth muscle cell apoptosis by a phosphatidylinositol 3 kinase-dependent pathway. Kidney Int, 2000. 58(1): p. 269-82.
83. Sasaki, R., S. Masuda, and M. Nagao, Erythropoietin: multiple physiological functions and regulation of biosynthesis. Biosci Biotechnol Biochem, 2000. 64(9): p. 1775-93.
84. Acs, G., et al., Erythropoietin and erythropoietin receptor expression in human cancer. Cancer Res, 2001. 61(9): p. 3561-5.
Oscar Vadas Page 59
Activation of the erythropoietin receptor by multivalent molecules
Introduction: Part II: Erythropoietin and erythropoiesis stimulating agents85. Li, F., Z.Z. Chong, and K. Maiese, Erythropoietin on a tightrope: balancing neuronal and vascular protection between intrinsic and extrinsic pathways. Neurosignals, 2004. 13(6): p. 265-89.
86. Rossert, J. and K.U. Eckardt, Erythropoietin receptors: their role beyond erythropoiesis. Nephrol Dial Transplant, 2005. 20(6): p. 1025-8.
87. Chang, S.C., D. Sikkema, and E. Goldwasser, Evidence for an erythropoietin receptor protein on rat bone marrow cells. Biochem Biophys Res Commun, 1974. 57(2): p. 399-405.
88. Krantz, S.B. and E. Goldwasser, Specific binding of erythropoietin to spleen cells infected with the anemia strain of Friend virus. Proc Natl Acad Sci U S A, 1984. 81(23): p. 7574-8.
89. Cheetham, J.C., et al., NMR structure of human erythropoietin and a comparison with its receptor bound conformation. Nat Struct Biol, 1998. 5(10): p. 861-6.
90. Livnah, O., et al., Crystallographic evidence for preformed dimers of erythropoietin receptor before ligand activation. Science, 1999. 283(5404): p. 987-90.
91. Remy, I., I.A. Wilson, and S.W. Michnick, Erythropoietin receptor activation by a ligand-induced conformation change. Science, 1999. 283(5404): p. 990-3.
92. D'Andrea, A.D., H.F. Lodish, and G.G. Wong, Expression cloning of the murine erythropoietin receptor. Cell, 1989. 57(2): p. 277-85.
93. Bailey, S.C., et al., Antipeptide antibodies as probes of the recombinant and endogenous murine erythropoietin receptors. Exp Hematol, 1993. 21(12): p. 1535-43.
94. Sawyer, S.T., The two proteins of the erythropoietin receptor are structurally similar. J Biol Chem, 1989. 264(22): p. 13343-7.
95. D'Andrea, A.D. and L.I. Zon, Erythropoietin receptor. Subunit structure and activation. J Clin Invest, 1990. 86(3): p. 681-7.
96. Youssoufian, H., et al., Structure, function, and activation of the erythropoietin receptor. Blood, 1993.
81(9): p. 2223-36.
97. Bazan, J.F., Structural design and molecular evolution of a cytokine receptor superfamily. Proc Natl Acad Sci U S A, 1990. 87(18): p. 6934-8.
98. Sawyer, S.T., S.B. Krantz, and E. Goldwasser, Binding and receptor-mediated endocytosis of erythropoietin in Friend virus-infected erythroid cells. J Biol Chem, 1987. 262(12): p. 5554-62.
99. Hitomi, K., et al., Erythropoietin receptor of a human leukemic cell line with erythroid characteristics.
Biochem Biophys Res Commun, 1988. 154(3): p. 902-9.
100. Mayeux, P., C. Billat, and R. Jacquot, Murine erythroleukaemia cells (Friend cells) possess high-affinity binding sites for erythropoietin. FEBS Lett, 1987. 211(2): p. 229-33.
101. Witthuhn, B.A., et al., JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin. Cell, 1993. 74(2): p. 227-36.
102. Tanner, J.W., et al., The conserved box 1 motif of cytokine receptors is required for association with JAK kinases. J Biol Chem, 1995. 270(12): p. 6523-30.
103. Constantinescu, S.N., et al., The erythropoietin receptor cytosolic juxtamembrane domain contains an essential, precisely oriented, hydrophobic motif. Mol Cell, 2001. 7(2): p. 377-85.
104. Zhang, M.Y., et al., A minimal cytoplasmic subdomain of the erythropoietin receptor mediates p70 S6 kinase phosphorylation. Exp Hematol, 2001. 29(4): p. 432-40.
105. Broudy, V.C., et al., Erythropoietin receptor characteristics on primary human erythroid cells. Blood, 1991. 77(12): p. 2583-2590.
106. Sawada, K., et al., Quantitation of specific binding of erythropoietin to human erythroid colony-forming cells. J Cell Physiol, 1988. 137(2): p. 337-45.
107. Fraser, J.K., F.K. Lin, and M.V. Berridge, Expression of high affinity receptors for erythropoietin on human bone marrow cells and on the human erythroleukemic cell line, HEL. Exp Hematol, 1988.
16(10): p. 836-42.
108. Yasuda, Y., et al., Erythropoietin regulates tumour growth of human malignancies. Carcinogenesis, 2003. 24(6): p. 1021-9.
109. Farrell, F. and A. Lee, The erythropoietin receptor and its expression in tumor cells and other tissues.
Oncologist, 2004. 9 Suppl 5: p. 18-30.
110. Udupa, K.B., Functional significance of erythropoietin receptor on tumor cells. World J Gastroenterol, 2006. 12(46): p. 7460-2.
111. Lai, S.Y. and J.R. Grandis, Understanding the presence and function of erythropoietin receptors on cancer cells. J Clin Oncol, 2006. 24(29): p. 4675-6.
112. Fandrey, J., Erythropoietin Receptors on Tumor Cells: What Do They Mean? Oncologist, 2008.
13(suppl_3): p. 16-20.
Page 60 Oscar Vadas
Activation of the erythropoietin receptor by multivalent molecules
Introduction: Part II: Erythropoietin and erythropoiesis stimulating agents113. Jelkmann, W., et al., The erythropoietin receptor in normal and cancer tissues. Crit Rev Oncol Hematol, 2008. 67(1): p. 39-61.
114. Wickrema, A., et al., Differentiation and erythropoietin receptor gene expression in human erythroid progenitor cells. Blood, 1992. 80(8): p. 1940-9.
115. Chin, K., et al., Production and processing of erythropoietin receptor transcripts in brain. Brain Res Mol Brain Res, 2000. 81(1-2): p. 29-42.
116. Verdier, F., et al., Proteasomes Regulate the Duration of Erythropoietin Receptor Activation by Controlling Down-regulation of Cell Surface Receptors. J. Biol. Chem., 2000. 275(24): p. 18375-18381.
117. Walrafen, P., et al., Both proteasomes and lysosomes degrade the activated erythropoietin receptor.
Blood, 2005. 105(2): p. 600-608.
118. Seubert, N., et al., Active and inactive orientations of the transmembrane and cytosolic domains of the erythropoietin receptor dimer. Mol Cell, 2003. 12(5): p. 1239-50.
119. Klingmuller, U., The role of tyrosine phosphorylation in proliferation and maturation of erythroid progenitor cells--signals emanating from the erythropoietin receptor. Eur J Biochem, 1997. 249(3): p.
637-47.
120. Miura, O., et al., Erythropoietin induces association of the JAK2 protein tyrosine kinase with the erythropoietin receptor in vivo. Blood, 1994. 84(5): p. 1501-7.
121. Tauchi, T., et al., Involvement of SH2-containing phosphotyrosine phosphatase Syp in erythropoietin receptor signal transduction pathways. J Biol Chem, 1995. 270(10): p. 5631-5.
122. Wilks, A.F., et al., Two novel protein-tyrosine kinases, each with a second phosphotransferase-related catalytic domain, define a new class of protein kinase. Mol Cell Biol, 1991. 11(4): p. 2057-65.
123. Gobert, S., et al., Identification of tyrosine residues within the intracellular domain of the erythropoietin receptor crucial for STAT5 activation. Embo J, 1996. 15(10): p. 2434-41.
124. Sawyer, S.T. and K. Penta, Association of JAK2 and STAT5 with erythropoietin receptors. Role of receptor phosphorylation in erythropoietin signal transduction. J Biol Chem, 1996. 271(50): p. 32430-7.
125. Chin, H., et al., Lyn physically associates with the erythropoietin receptor and may play a role in activation of the Stat5 pathway. Blood, 1998. 91(10): p. 3734-45.
126. Barber, D.L., et al., A common epitope is shared by activated signal transducer and activator of transcription-5 (STAT5) and the phosphorylated erythropoietin receptor: implications for the docking model of STAT activation. Blood, 2001. 97(8): p. 2230-7.
127. Ihle, J.N., The Stat family in cytokine signaling. Curr Opin Cell Biol, 2001. 13(2): p. 211-7.
128. Silva, M., et al., Erythropoietin can induce the expression of bcl-x(L) through Stat5 in erythropoietin-dependent progenitor cell lines. J Biol Chem, 1999. 274(32): p. 22165-9.
129. Fisher, J.W., A quest for erythropoietin over nine decades. Annu Rev Pharmacol Toxicol, 1998. 38: p.
1-20.
130. Xia, K., et al., The cytokine-activated tyrosine kinase JAK2 activates Raf-1 in a p21ras-dependent manner. Proc Natl Acad Sci U S A, 1996. 93(21): p. 11681-6.
131. Sui, X., et al., Synergistic activation of MAP kinase (ERK1/2) by erythropoietin and stem cell factor is essential for expanded erythropoiesis. Blood, 1998. 92(4): p. 1142-9.
132. Mason, J.M., et al., The SH2 inositol 5-phosphatase Ship1 is recruited in an SH2-dependent manner to the erythropoietin receptor. J Biol Chem, 2000. 275(6): p. 4398-406.
133. Damen, J.E., et al., Phosphorylation of tyrosine 503 in the erythropoietin receptor (EpR) is essential for binding the P85 subunit of phosphatidylinositol (PI) 3-kinase and for EpR-associated PI 3-kinase activity. J Biol Chem, 1995. 270(40): p. 23402-8.
134. Damen, J.E., et al., Phosphatidylinositol 3-kinase associates, via its Src homology 2 domains, with the activated erythropoietin receptor. Blood, 1993. 81(12): p. 3204-10.
135. He, T.C., et al., Association of the p85 regulatory subunit of phosphatidylinositol 3-kinase with an essential erythropoietin receptor subdomain. Blood, 1993. 82(12): p. 3530-8.
136. Mayeux, P., et al., Erythropoietin induces the association of phosphatidylinositol 3'-kinase with a tyrosine-phosphorylated protein complex containing the erythropoietin receptor. Eur J Biochem, 1993.
216(3): p. 821-8.
137. Jaster, R., T. Bittorf, and J. Brock, Involvement of phosphatidylinositol 3-kinase in the mediation of erythropoietin-induced activation of p70S6k. Cell Signal, 1997. 9(2): p. 175-9.
138. Bunn, H.F., New agents that stimulate erythropoiesis. Blood, 2007. 109(3): p. 868-873.
Oscar Vadas Page 61
Activation of the erythropoietin receptor by multivalent molecules
Introduction: Part II: Erythropoietin and erythropoiesis stimulating agents139. Juul, S. and U. Felderhoff-Mueser, Epo and other hematopoietic factors. Seminars in Fetal and Neonatal Medicine, 2007. 12(4): p. 250-258.
140. Schellekens, H., The first biosimilar epoetin: but how similar is it? Clin J Am Soc Nephrol, 2008. 3(1):
p. 174-8.
141. Mikhail, A., A. Covic, and D. Goldsmith, Stimulating erythropoiesis: future perspectives. Kidney Blood Press Res, 2008. 31(4): p. 234-46.
142. Halstenson, C.E., et al., Comparative pharmacokinetics and pharmacodynamics of epoetin alfa and epoetin beta. Clin Pharmacol Ther, 1991. 50(6): p. 702-12.
143. Acharya, V.N., et al., Effect of low dose recombinant human omega erythropoietin (rHuEPO) on anaemia in patients on hemodialysis. J Assoc Physicians India, 1995. 43(8): p. 539-42.
144. Sikole, A., et al., Epoetin omega for treatment of anemia in maintenance hemodialysis patients. Clin Nephrol, 2002. 57(3): p. 237-45.
145. Bren, A., et al., A comparison between epoetin omega and epoetin alfa in the correction of anemia in hemodialysis patients: a prospective, controlled crossover study. Artif Organs, 2002. 26(2): p. 91-7.
146. Spinowitz, B.S. and R.D. Pratt, Epoetin delta is effective for the management of anaemia associated with chronic kidney disease. Curr Med Res Opin, 2006. 22(12): p. 2507-13.
147. Martin, K.J., The first human cell line-derived erythropoietin, epoetin-delta (Dynepo), in the management of anemia in patients with chronic kidney disease. Clin Nephrol, 2007. 68(1): p. 26-31.
148. Kwan, J.T. and R.D. Pratt, Epoetin delta, erythropoietin produced in a human cell line, in the management of anaemia in predialysis chronic kidney disease patients. Curr Med Res Opin, 2007.
23(2): p. 307-11.
149. Martin, K.J., Epoetin delta in the management of renal anaemia: results of a 6-month study. Nephrol Dial Transplant, 2007. 22(10): p. 3052-4.
150. Llop, E., et al., Structural analysis of the glycosylation of gene-activated erythropoietin (epoetin delta,
150. Llop, E., et al., Structural analysis of the glycosylation of gene-activated erythropoietin (epoetin delta,